Context dependent substitution biases vary within the human genome

Background: Models of sequence evolution typically assume that different nucleotide positions evolve independently. This assumption is widely appreciated to be an over-simplification. The best known violations involve biases due to adjacent nucleotides. There have also been suggestions that biases exist at larger scales, however this possibility has not been systematically explored. Results: To address this we have developed a method which identifies over- and under-represented substitution patterns and assesses their overall impact on the evolution of genome composition. Our method is designed to account for biases at smaller pattern sizes, removing their effects. We used this method to investigate context bias in the human lineage after the divergence from chimpanzee. We examined bias effects in substitution patterns between 2 and 5 bp long and found significant effects at all sizes. This included some individual three and four base pair patterns with relatively large biases. We also found that bias effects vary across the genome, differing between transposons and non-transposons, between different classes of transposons, and also near and far from genes. Conclusions: We found that nucleotides beyond the immediately adjacent one are responsible for substantial context effects, and that these biases vary across the genome

Systematic review of global functioning and quality of life in people with psychotic disorders

Aims People with psychotic disorders face impairments in their global functioning and their quality of life (QoL). The relationship between the two outcomes has not been systematically investigated. Through a systematic review, we aim to explore the presence and extent of associations between global functioning and QoL and establish whether associations depend on the instruments employed.Methods In May 2016, ten electronic databases were searched using a two-phase process to identify articles in which associations between global functioning and QoL were assessed. Basic descriptive data and correlation coefficients between global functioning and QoL instruments were extracted, with the strength of the correlation assessed according to the specifications of Cohen 1988. Results were reported with reference to the Meta-analysis of Observational Studies in Epidemiology guidelines and PRISMA standards. A narrative synthesis was performed due to heterogeneity in methodological approaches.Results Of an initial 15 183 non-duplicate articles identified, 756 were deemed potentially relevant, with 40 studies encompassing 42 articles included. Fourteen instruments for measuring global functioning and 22 instruments for measuring QoL were used. Twenty-nine articles reported linear associations while 19 assessed QoL predictors. Correlations between overall scores varied in strength, primarily dependent on the QoL instrument employed, and whether QoL was objectively or subjectively assessed. Correlations observed for objective QoL measures were consistently larger than those observed for subjective measures, as were correlations for an interviewer than self-assessed QoL. When correlations were assessed by domains of QoL, the highest correlations were found for social domains of QoL, for which most correlations were moderate or higher. Global functioning consistently predicted overall QoL as did depressive and negative symptoms.Conclusions This review is the first to explore the extent of associations between global functioning and QoL in people with psychotic disorders. We consistently found a positive association between global functioning and QoL. The strength of the association was dependent on the QoL instrument employed. QoL domains strongly associated with global functioning were highlighted. The review illustrates the extensive array of instruments used for the assessment of QoL and to a lesser extent global functioning in people with psychotic disorders and provides a framework to understand the different findings reported in the literature. The findings can also inform the future choice of instruments by researchers and/or clinicians. The observed associations reassure that interventions for improving global functioning will have a positive impact on the QoL of people living with a psychotic disorder

Growth Endocrine Axis and Bovine Chromosome 5: Association of SNP Genotypes and Reproductive Phenotypes in an Angus, Brahman and Romosinuano Diallele

The growth endocrine axis influences reproduction. A QTL associated with enhanced ovulation exists on chromosome 5 in cattle and there are 6 genes underlying this region involved in the mechanisms of GH action. Resequencing exons, 5’ and 3’ untranslated regions and conserved non-coding regions of these genes in a multibreed resource population revealed 75 SNP usable for genotype to phenotype association studies. In the current study, phenotypes included age at first calving, calving interval, days to calving, and pregnancy rate. Data were collected from developing heifers (n = 650) of a diallele composed of Angus, Brahman, and Romosinuano breeds. A SNP in the promoter of the signal transducer and activator of transcription (STAT)2 gene, which is a second messenger of GH, had minor allele frequency \u3e 10% across the three breeds. This SNP did not deviate from Hardy- Weinberg equilibrium (X2 = 1.00, P \u3e 0.31), so deemed useful for genotype to phenotype association analyses. Since the remaining SNP appeared to predict breed, they were used to correct for population stratification using STRUCTURE, which revealed three distinctive ancestral clusters. No significant association was detected between the STAT2 genotype and reproductive traits in mixed effects analyses using genotype as a fixed term, sire as a random term, and coefficient of ancestry as a covariate; however, the interaction of SNP genotype and ancestral cluster was associated with the traits days to calving (P \u3c 0.05) and calving interval (P \u3c 0.10). Interaction plots revealed a higher estimated effect of heterozygous genotype in cluster 1 (inferred primarily from Brahman) and lower estimates in clusters 2 and 3 (inferred primarily from Bos taurus). The heterozygous genotype extended these trait levels ~100 d. A SNP in the promoter of the STAT2 gene was associated with fertility trait levels in admixed cows of the breeds Angus, Brahman, and Romosinuano. The effect appeared to be a non-additive genetic relationship as heterozygous genotype extended levels of traits indicative of postpartum rebreeding

The Earlier the Better: Structural Analysis and Separation of Lanthanides with Pyrroloquinoline Quinone

Lanthanides (Ln) are critical raw materials, however, their mining and purification have a considerable negative environmental impact and sustainable recycling and separation strategies for these elements are needed. In this study, the precipitation and solubility behavior of Ln complexes with pyrroloquinoline quinone (PQQ), the cofactor of recently discovered lanthanide (Ln) dependent methanol dehydrogenase (MDH) enzymes, is presented. In this context, the molecular structure of a biorelevant europium PQQ complex was for the first time elucidated outside a protein environment. The complex crystallizes as an inversion symmetric dimer, Eu2PQQ2, with binding of Eu in the biologically relevant pocket of PQQ. LnPQQ and Ln1Ln2PQQ complexes were characterized by using inductively coupled plasma mass spectrometry (ICP‐MS), infrared (IR) spectroscopy, 151Eu‐Mössbauer spectroscopy, X‐ray total scattering, and extended X‐ray absorption fine structure (EXAFS). It is shown that a natural enzymatic cofactor is capable to achieve separation by precipitation of the notoriously similar, and thus difficult to separate, lanthanides to some extent

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

Expression of a Serine Protease Gene prC Is Up-Regulated by Oxidative Stress in the Fungus Clonostachys rosea: Implications for Fungal Survival

BACKGROUND: Soil fungi face a variety of environmental stresses such as UV light, high temperature, and heavy metals. Adaptation of gene expression through transcriptional regulation is a key mechanism in fungal response to environmental stress. In Saccharomyces cerevisiae, the transcription factors Msn2/4 induce stress-mediated gene expression by binding to the stress response element. Previous studies have demonstrated that the expression of extracellular proteases is up-regulated in response to heat shock in fungi. However, the physiological significance of regulation of these extracellular proteases by heat shock remains unclear. The nematophagous fungus Clonostachys rosea can secret an extracellular serine protease PrC during the infection of nematodes. Since the promoter of prC has three copies of the stress response element, we investigated the effect of environmental stress on the expression of prC. METHODOLOGY/PRINCIPAL FINDINGS: Our results demonstrated that the expression of prC was up-regulated by oxidants (H(2)O(2) or menadione) and heat shock, most likely through the stress response element. After oxidant treatment or heat shock, the germination of conidia in the wild type strain was significantly higher than that in the prC mutant strain in the presence of nematode cuticle. Interestingly, the addition of nematode cuticle significantly attenuated the production of reactive oxygen species (ROS) induced by oxidants and heat shock in the wild type strain, but not in prC mutant strain. Moreover, low molecule weight (<3 kD) degradation products of nematode cuticle suppressed the inhibitory effect of conidial germination induced by oxidants and heat shock. CONCLUSIONS/SIGNIFICANCE: These results indicate that PrC plays a protective role in oxidative stress in C. rosea. PrC degrades the nematode cuticle to produce degradation products, which in turn offer a protective effect against oxidative stress by scavenging ROS. Our study reveals a novel strategy for fungi to adapt to environmental stress

Soil bacterial and fungal communities across a pH gradient in an arable soil

Soils collected across a long-term liming experiment (pH 4.0-8.3), in which variation in factors other than pH have been minimized, were used to investigate the direct influence of pH on the abundance and composition of the two major soil microbial taxa, fungi and bacteria. We hypothesized that bacterial communities would be more strongly influenced by pH than fungal communities. To determine the relative abundance of bacteria and fungi, we used quantitative PCR (qPCR), and to analyze the composition and diversity of the bacterial and fungal communities, we used a bar-coded pyrosequencing technique. Both the relative abundance and diversity of bacteria were positively related to pH, the latter nearly doubling between pH 4 and 8. In contrast, the relative abundance of fungi was unaffected by pH and fungal diversity was only weakly related with pH. The composition of the bacterial communities was closely defined by soil pH; there was as much variability in bacterial community composition across the 180-m distance of this liming experiment as across soils collected from a wide range of biomes in North and South America, emphasizing the dominance of pH in structuring bacterial communities. The apparent direct influence of pH on bacterial community composition is probably due to the narrow pH ranges for optimal growth of bacteria. Fungal community composition was less strongly affected by pH, which is consistent with pure culture studies, demonstrating that fungi generally exhibit wider pH ranges for optimal growth. The ISME Journal (2010) 4, 1340-1351; doi: 10.1038/ismej.2010.58; published online 6 May 2010&nbsp

La educación inclusiva frente a las desigualdades sociales: un estado de la cuestion y algunas reflexiones geograficas

Este artículo establece un estado de la cuestión e la educación inclusiva en el mundo y sugiere algunas reflexiones al respecto. El primer apartado recuerda las conexiones ineludibles entre las preocupaciones educativas por la educación inclusiva y las preocupaciones más generales por la desigualdad. El segundo consigna los criterios de búsqueda de las publicaciones académicas, y observa dos grandes temas en sus contenidos: sobre todo, el cambio interno de las escuelas atrae las miradas, pero en segundo plano también el entorno territorial despierta algunas inquietudes. El tercero anota los criterios de búsqueda de la documentación del Banco Mundial, la OCDE y la UNESCO. En este ámbito los simposios de la Oficina Internacional de la Educación de UNESCO revelan una interpretación dispar, aunque convergente, del concepto de educación inclusiva en las distintas regiones mundiales. Asimismo, todas las publicaciones oficiales muestran una atención prioritaria a las dinámicas internas de las escuelas, puesto que apenas algunas esbozan ciertas relaciones entre la educación inclusiva y las políticas públicas. El último apartado adelanta varios argumentos a favor de una mayor consideración de las escalas local y estatal de la educación inclusiva. Las principales razones para atender a la dimensión local provienen de la causalidad acumulativa de las privaciones sociales, de la necesidad de articular la acción de las escuelas y de la posibilidad de abrir un espacio significativo para la participación ciudadana. Asimismo, las principales razones para atender a la dimensión estatal surgen de las posibles sinergias entre la educación inclusiva y la expansión educativa (p. ej. ¿es correlativo el avance de la escolarización en los distintos ciclos escolares?) como también entre la educación inclusiva y la protección social (p. ej. ¿tienen una implicación pedagógica consistente las abundantes condiciones educativas de las transferencias sociales?

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)